title: Enterococcal and streptococcal resistance to PC190723 and related compounds: molecular insights from a FtsZ mutational analysis.
abstract: New antibiotics with novel mechanisms of action are urgently needed to overcome the growing bacterial resistance problem faced by clinicians today. PC190723 and related compounds represent a promising new class of antibacterial compounds that target the essential bacterial cell division protein FtsZ. While this family of compounds exhibits potent antistaphylococcal activity, they have poor activity against enterococci and streptococci. The studies described herein are aimed at investigating the molecular basis of the enterococcal and streptococcal resistance to this family of compounds. We show that the poor activity of the compounds against enterococci and streptococci correlates with a correspondingly weak impact of the compounds on the self-polymerization of the FtsZ proteins from those bacteria. In addition, computational and mutational studies identify two key FtsZ residues (E34 and R308) as being important determinants of enterococcal and streptococcal resistance to the PC190723-type class of compounds.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA.
authors.forename: Malvika
authors.initials: M
authors.lastname: Kaul
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Parhi
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Lavoie
authors.forename: Steve
authors.initials: S
authors.lastname: Tuske
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: John E
authors.initials: JE
authors.lastname: Kerrigan
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D055503:Protein Multimerization; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles
keywords: Antibacterial compounds; Bacterial resistance; FtsZ polymerization; FtsZ-targeting drugs; MRSA